GENETIC SUSCEPTIBILITY TO PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Polychlorinated biphenyls (PCBs) are persistent organic pollutants that bio-accumulate in the food chain and cause a number of adverse health effects including learning and memory deficits in children exposed in utero and during lactation. The principal investigator's previous research in mice uncovered two genes that increase susceptibility to developmental PCB exposure  the aryl hydrocarbon receptor (Ahr) and cytochrome P450 1A2 (Cyp1a2), a gene directly regulated by the AHR. Coplanar PCBs bind to the AHR, triggering changes in gene expression. Many of these AHR-regulated genes are involved in central nervous system development. AHR activation was also recently shown to affect the activity of DNA methylases. The glucocorticoid receptor is well known to be regulated by differential methylation, and changes in receptor levels can alter learning, memory and the response to stress. Interestingly, many pollutants that bind to the AHR produce changes in stress hormone levels or an animal's response to stress. This project was designed to test the hypothesis that persistent activation of the AHR alters normal brain development and the response to stress via epigenetic mechanisms. The specific aims were to: 1.) Compare corticosterone levels, anxiety and response to stress in PCB-treated and control animals differing at the Ahr and Cyp1a2 loci. 2.) Determine if developmental PCB exposure alters gene-specific DNA methylation patterns in the hippocampus, cortex and hypothalamus.